NURS 371 Pathophysiology Unit 1 notes
NURS 371 Pathophysiology Unit 1 notes 371
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This 28 page Class Notes was uploaded by Ally Marcello on Tuesday September 6, 2016. The Class Notes belongs to 371 at Catholic University of America taught by O'Brian, Sandra in Fall 2016. Since its upload, it has received 69 views. For similar materials see Pathophysiology in NURSING at Catholic University of America.
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Date Created: 09/06/16
Pathophysiology Prof. O’Brian Sept, 2, 2016 Unit 1: Cell Structure Prokaryote vs Eukaryote Prokaryote Eukaryote No distinct nucleus (single, circular Complex cellular organization chromosome) Lack histones, organelles Membrane-bound organelles Include Cyanobacteria, bacteria, and Well-defined nucleus with several rickettsiae chromosomes Higher animals, plants, fungi, protozoa, and algae Differences in biochemical activity o Protein synthesis o Transport across outer membrane o Enzyme content Eukaryotes can be matured into one of the 8 different categories o Movement (muscle cells) o Conductivity (nerves) o Metabolic absorption (cells of the intestines) o Secretion o Excretion o Respiration (lung cells) o Reproduction (gametes) o Communication Eukaryotic cell o Consists of a plasma membrane, cytoplasm (fluid filling), and membrane bound intracellular organelles Note: Intra is inside, inter is in between Nucleus- membrane bound, and it is the largest membrane bound organelle Responsible for cell division and containing the transmission of genetic information Located in the center of the cell Has 2 pliable membranes that compose the nuclear envelope Pores allow chemical messages to enter and exit the nucleus o Histones compress and fold the chromosomes to reduce the change of chromosomes breaking Contains a nucleolus (small dense structure composed mostly of ribonucleic acid, most of the cellular DNA, and the DNA-binding proteins that regulate activity Cytoplasm Fluid that is within the plasma membrane The matrix is made of cytosol, proteins, enzymes and fibers. o Storage unit for fat and carbohydrates and secretory vesicles Contains all of the organelles Ribosomes Made in the nucleolus RNA protein complexes that are important for cellular protein synthesis Endoplasmic Reticulum o Specialized in synthesis and transport of proteins (rough ER) and lipids (smooth ER) Rough ER is studded with ribosomes along the walls Smooth lacks ribosomes so naturally it synthesizes lipids Golgi Complex o Network of smooth membranes that mainly process and package proteins to vesicles to be transported to other part of the cell/other cells o Look like stacked pancakes inside the cell where little vesicles bud off and deliver proteins Cytoskeleton o Composed of networks of protein filaments, microtubules and actin filaments Help to form Microvilli, cilia and flagella o Helps maintain structure of the cell through the filaments Lysosomes o Originate from the golgi o Contain digestion enzymes o When there is cellular injury, it releases enzymes that results in cellular self-destruction o More for digestion of cellular bodies Peroxisomes o Contain digestive enzymes (oxidase) and they break down waste products in the cell into harmless substances Mitochondria o Powerhouse of the cell because that’s where the energy is created o Adenosine triphosphate is the cellular energy created Have enzymes in the electron transport chain in the matrix of the mitochondria o Role in osmotic regulation- how water transported inside and outside of the cell, pH control Calcium homeostasis cell signaling Caveolae o They are small indentations that can capture extracellular material and important in transporting materials across the cell membrane Vaults o Octagonal barrels and are capable of transporting substances across the cell Plasma membrane Gives the cell its shape It is a barrier, has gates, channels, and pumps Determines what comes in and out of the cell Also is part of cell-to-cell communication through cellular junctions Composition o It has a phospholipid bilayer that is always fluid and moving Amphipathic (both hydrophobic (tail) and hydrophilic (head)) Allows O2 and CO2 to diffuse readily lipid layer has three different phases: solid-gel phase, fluid-liquid crystalline phase, liquid-ordered phase Changes based on physiological factors such as temperature and pressure fluctuations Lipids act as molecular glue and the membrane is maintained in place Lipid rafts have 4 impt functions Cellular polarity and organization of signaling trafficking Acting as platforms for extracellular matrix adhesion and intracellular cytoskeletal tethering to the plasma membrane Enabling signaling across membranes that can rearrange cytoskeletal architecture, and regulate cell growth, migration and other functions Allowing entry of viruses, bacteria, toxins and nanoparticles. Proteins of the plasma membrane At least 20 different types of amino acids, and each protein has a its own amino acid ‘recipe’ Workhorse of the cell Translated (synthesis from RNA by ribosomes) o posttranslational modifications are methods used to diversify the #of proteins generated the modifications alter the activity and function of proteins Functions o Receptors o Enzymes o Transport channels/carriers o Surface markers (glycoproteins) that identify a cell to its neighbor o Cell adhesion molecules (CAMs)- proteins that allow cells to link together and for attachments of the cytoskeleton for maintaining cell shape o Catalysts of chemical reactions Protein homeostasis o Important within a cell o # of copies is determined by how fast they are made and how long it survive or is broken down. o Main role is to make sure there are minimal protein misfolding regulated by ribosomes (makers), Chaperones (helpers), Proteolytic systems which include lysosomes and ubiquitin proteasome system (UPS) When homeostasis breaks down it can have an effect on human pathology and cause disease Carbohydrates of the plasma membrane have several functions Protection Lubrication which assists in mobility of other cells (like leukocytes) cell to cell recognition of extracellular substances adhesion Cellular receptors can recognize and bind with: Ligands o Bind with cellular receptors to activate or inhibit the receptor’s associated signaling or biochemical pathway o Binding site is where ligand and the protein meet (hormones are ligands lock and key model, selective bonding) Plasma membrane receptors determine response based on when the action of binding takes place, then other biochemical processes begin Cell-to-cell adhesions Cells-> tissues organs Held together by o Extracellular membrane o Cell adhesion molecules o Specialized cell junctions Extracellular matrix o Integrated meshwork of fibrous proteins embedded in a watery gel like fluid made of complex carbohydrates When it is excreted by the cell it provides a pathway for diffusion of nutrients, waste and other water soluble substances between blood and tissue cells o Macromolecules o Collagen- forms cable like fibers or sheets to provide strength and resistance o longitudinal stress Osteoarthritis destroys collagen fiber o Elastin- rubber like protein fiber and it is capable of stretching and recoiling o Fibronectin- helps cells adhere to each other and anchor to the basement membrane If the BM isn’t in the right composition it leaves it open to the transmission of cancer cells. o The ETM is excrete by fibroblasts These connect cells to form the tissues and organs, this is connective tissue Can be very hard (bone), to squishy (in the eye) Responsible for cell growth and differentiation Cell junctions o Some hold cells together to form a tight seal (tight junction), some provide strong mechanical connections (desmosomes), come are capable of chemical communication (gap) cells can stick together and communicate, and some keep the polarity of the cell (pumps) o Can be classified as symmetrical (attach to others symmetrically, two-way connection) Desmosomes- ells that form continuous bands of epithelial or sheets- help to maintain structural integrity. Has two different kinds o Belt- literally looks like a belt around the cell o Spot- look like hemidesmosomes but connect cell to cell Tight junctions- barriers to diffusion, and prevent the movement of substances through transport proteins and prevent leakage of the small molecules Gap junction- clusters of communicating tunnels or connections, allow small ions and molecules to pass in from one cell to another o Asymmetrical (one-way connection) Hemidesmosomes- attaches one cell to the ECM, so it is asymmetrical and are found in epithelial (basal) cells to the basement lamina Gating o uninjured cells protect themselves from calcium when neighbors are injured and release the Ca+ (blocking the calcium from entering it) Cell communication o Cells communicate in 3 main ways They display plasma membrane-bound receptors that affect the cell itself and other cells in direct physical contact They affect cell receptor proteins inside the target cell and the signal molecule has to enter the cell to bind to them They form protein channels (gap junction) that directly coordinate the activities of the adjacent cell o Alterations I cellular communication affect disease onset and progression o Chemical signaling Contact dependent (usually local signaling) Requires cells to be in close contact Paracrine Cells secrete local chemical mediators that are quickly taken u, destroyed, or immobilized Usually involves different cell types Autocrine signaling Secretion targets itself o Hormonal Involves specialized endocrine cells that secrete hormones they travel through the bloodstream to produce a response in other sets of cells Neurohormonal Hormones are released into the blood by neurosecretory neurons Secrete blood borne chemical messengers, whereas ordinary neurons secrete short-range neurotransmitters into a small space called a synapse o These neurotransmitters travel across synaptic clefts and acts on postsynaptic target cells Signal transduction pathways are communication pathways, or signaling cascades. Signals are passed between cells when a certain type of molecule is produced by one cell, signal cell, then received by another, the target cell, by means of a receptor protein which then stimulates a signal cascade in the target cell in order to produce the appropriate response (i.e. growth, die, differentiate) o Cell Metabolism o Metabolism- all of the chemical tasks that are carried out within a cell in order to maintain essential cell function o Anabolism Energy using process o Catabolism Energy making/releasing process Takes place in 3 phases talked about later Different catabolic pathways for different molecules Proteins amino acids (then eventually acetyl CoA) Fats fatty acids (then eventually acetyl CoA) Glucose pyruvate ATP found outside of the cell as well because it has a role in messaging o Adenosine Triphosphate (ATP) The energy byproduct of the catabolism Fuel for cell survival Used in synthesis, contraction, and active transport Stored and transferred within the cell Takes place within the mitochondria o Cell Energy Takes place in 3 different phases 1. Mechanical digestion of food from large molecules to small molecules outside of the cell and are activated by secreted enzymes o Turns proteins into amino acids, polysaccharides into monosaccharaides, and fats into fatty acids and glycerol 2. Glycolysis and oxidation- most important part is glycolysis. Intracellular breakdown of the polysaccharide sugars into pyruvic acid. Yields 2 ATP for every molecule of glucose 3. Citric acid or Krebs cycle-Most of the ATP is made in this phase whch begins with the CAC and ended with oxidative phosphorylation o When there is a high presence of O (A2robic) the pyruvate enters the Krebs cycle which creates many ATP o Then there is a low presence of oxygen (Anaerobic pathway) the pyruvic acid turns into lactic acid (this is what causes cramps when running!); accompanied by production of limited ATP High O 2 high ATP Low O 2 low ATP o Equation for Krebs cycle with a lot of oxygen: C6H 12+66 O 2 CO2 + 6 H2O + 36-38 ATP o *Lactic acid pathway leads to only 2 ATP Call Transportation o How do substances more from point A to point B inside or outside of the cell o Membrane Transport Cells are continually taking in nutrients fluids and chemical messengers from outside the cell or releasing the products of metabolism and lysosomal digestion A lot of substances in the cell are transported through simple diffusion (O2 and CO2) going from high concentration to low concentration with no energy, but a majority are transported by means of special membrane transport proteins These are embedded in the lipid bilayer and they transport select molecules with 2 major types of proteins o Transporters Allowing only those ions that fi the unique binding sites on the proteins (lock and key) o channels when open, forms a pore that crosses the lipid bilayer that allows certain ions and selective polar organic molecules pass based on size and charge play an important role in electrical exciting in the nerves and muscle cells Passive transport Requires no energy because molecules move easily form areas of high concentration to low concentration o Ex: Osmosis, diffusion, and hydrostatic pressure o Diffusion Movement of solutes from higher concentration to lower concentration Ca+, K+, and Na+ diffuse across the membrane slowly because of the positive charge of the pores, they repel each other The more soluble it is in oils, or smaller, they are going to go through pores faster O 2 H 2, and CO d2ffuse rapidly because they aren’t charged o Filtration: Hydrostatic Pressure Movement of water and solutes through a membrane due to greater pushing pressure (force) on one side of the membrane than the other Hydrostatic pressure is the mechanical force of water pushing against cellular membranes (ex for vascular system is HBP) o The force of water when it pushes on cell membranes higher on one side, then water and other particles will move with the water t balance the pressure. o Blood pressure is an example of hydrostatic pressure- the heart contracts and the hydrostatic pressure within the capillary bed reaches 25-30 mm Hg. o Osmosis Movement of water down a concentration gradient across a semipermeable membrane For osmosis to occur o 1) Membrane must be more permeable to water than solutes o 2) Concentration of solutes on one side greater than the other o Affected by hydrostatic pressure and ion concentration but not particle size or weight Osmolality controls the water and its distribution throughout the body and its compartments o Concentration of water molecules by weight (normal of body fluids is 280-290 osm/kg) o Isotonic- concentration of particles equals concentration of water on each side of the cell membrane (hypertonic means more particles outside, hypotonic= Less molecules in the fluid surrounding the RBC) Osmolality Measures the number of milliosmoles per kilogram (mOsm/kg) of water o Concentration of molecules per weight of water preferred for human clinical assessment because osmolality will be greater than osmolarity due to the contents of the plasma Osmolarity Measures the number of milliosmoles per liter of solution o Concentration of molecules per volume of solution Active Needs energy because molecules flow “uphill” from areas of low concentration to areas of high concentration o Pumps, endocytosis, exocytosis Uniport where 1 molecule is moved across the membrane in one direction; uses plasma transporter Symport: where 2 molecules move across the membrane in the same direction at the same time Antiport is the movement of 2 molecules across the membrane in different directions simultaneously (sodium potassium pump) needs energy o 60-70% of all ATP made by the cell is used for active transport Electrolytes (95% of all the solutes in body fluids) are charged (cations + vs anions - ) Cations (PAWsitive): sodium (extracellular fluid) and potassium (intracellular fluid) o The differences in concentrations of Extracellular ions and intracellular ions facilitates electrical impulses across the membrane Transport by vesicle formation Transport of macromolecules need assistance to get through the membrane Endocytosis- brings substances inside the cell o forms a pocket, enfolds the macromolecule and pulls it inside the cell. Once the vesicle moves inside the cell, they are ingested through Pinocytosis (cell drinking) or phagocytosis (cell eating) o Endo= in Exocytosis- brings substances out of the cell o substance is enveloped inside a vesicle (from the ER or golgi) which fuses with the plasma membrane and the contents are released outside. o Exo= exit/out o 2 jobs for exocytosis: Replace plasma membrane removed from endocytosis and to release those substances to the extracellular matrix o Electrical impulses All body cells are polarized (inside more negative than outside) Resting membrane potential- Difference between the charges due to composition of ions in the fluids Antiport helps to maintain this composition K+ diffuses more easily from inside to outside Action potential- When a rapid change happens in the resting potential Depolarization- When the electrical stimuli occur, the cells become more permeable to sodium, so Na+ moves into the cell. At this point, the cell becomes neutral (no charge). Cell has to reach threshold potential for the signal to be passed on (generally has to depolarize to 15-20 millivolts) Repolarization- When electrical activity passes, the pumps pump sodium back out to reestablish the resting potential. After repolarization, the cell is exhausted and will not respond to any electrical stimuli (absolute refractory period) When the membrane potential is more negative than normal (due to decreased K+ levels in the cell), the cell is in the hyperpolarized state so a stronger than normal stimulus is needed to reach threshold potential and generate an action potential Cell Reproduction Somatic cells that use mitosis The cell cycle o Takes place in 2 phases Mitosis Nuclear division Cytokinesis cytoplasmic division o S 1-2ynthesis of DNA in the nucleus o G 2 RNA and protein synthesis checkpoint o M mitosis (nuclear division and cytoplasmic division- most active part) o G 1 phase between M phase and Synthesis phase. Longest pause G1/s checkpoint- cell runs check to see if they are the right side, enough nutrients, receive growth factor signaling or DNA damage Mitosis (M phase) o Prophase Nuclear envelope breaks. First appearance of the chromosomes. Chromosomes separate into 2 sister chromatids. Spindle fibers appear and radiate from centrioles as the centrioles move to opposite poles of the cell o Metaphase Sister chromatids line up in the middle of the cell (equatorial plate) with microtubule spindles attached o Anaphase Microtubules begin to separate and pull the sister chromatids to separate sides of the cell (diploid number of chromosomes (46) 2n on each pole of the cell) o Telophase New nuclear membrane forms around the 46 chromosomes. The plasma membrane begins to pinch inward and a new membranes begin to form. Cytokinesis occurs. o Result: barring any errors, 2 identical daughter cells with the diploid number of chromosomes (46) Influences on the Cell cycle o Cellular division rates is about 12-24 hours (1 hr for mitosis and cytokinesis) o Fastest replicating cells are most affected by chemo therapy (mouth, tongue, hair) o Difference is length of G1 phase for different types of cells o Rates depend on: Protein growth factors (cytokines) Transmit signals within and between cells Govern the proliferation of cell types and they have roles regarding cell growth, but it depends on the body’s need. o If there is a need for more rapid replication of cells in one area, another area of the body will have to slow its replication because the body only has so many resources Genetic factors Epigenetic factors Heritable conditions, or changes in genome functions, that are without alterations in the DNA sequence o Once again… Cytokines are peptides that transmit signals within and outside the cell. Get signals from their closest neighbor and these signals can overcome intercellular breaking mechanisms that would otherwise restrain cell growth Certain set pattern cells follow for growth, but growth factors help encourage cells to speed up the process of the cell cycle Tissue formation o Cells work in colonies and find themselves in an environment of an Extracellular matrix which holds the cell together with a network of interaction To form tissues, cells must exhibit intercellular recognition and communication, adhesion, and memory. o Tissues differentiation is signaled by gene expression and DNA and RNA formation which governs proteins o Terminally differentiated (fully specialized) cells are regenerated from proliferating precursor stem cells o Stem cells have the potential to become anything o 4 main categories of tissues Nerves Highly specialized cells that transmit messages throughout the body Epithelial Covers most of the internland external body surfaces Is the lining for blood vessels, hollow organs, glands, digestive tract, linings of anus and urethra on male Connective Bind tissue and organs together; 4 types o Adipose o Bone o Fibrous o cartilaginous Muscle composed of myocytes enables movement CHAPTER 3 Epigenetics and Disease Epigenetics the study of changes in organisms caused by modification of gene expression o phenotype- physical appearance of the organism o genotype- what is written in the DNA. o Genetics has to do with alterations of the genes itself, epigenetics has to do with the alterations of the interpretations of the DNA sequence Results in change of the phenotype o There are mechanisms that turn genes on and off- genes are called silenced/not expressed if turned off. Happens during transcription (RNA) or during translation (synthesis of polypeptides in ribosomes) Environmental stresses have effects Epigenetic Mechanisms o DNA methylation When a methyl group is added to a cytosine at an abnormal position, gene expression is silenced Enhanced gene expression when methyl group is removed For example: for each cell of a normal human female, 1 of 2 X chromosomes is silenced by dense methylation and associated molecular marks, while the other is transcriptionally active and largely devoid of methylation Aberrant methylation can lead to misregulation of tumor- suppressing genes, so if something happens to those genes, tumors can develop. When a gene becomes heavily methylated the DNA is least likely to be transcripted by the RNA Aberrant methylation can lead to tumor formation which is one reason for an inherited colon cancer Normal methylation can keep tumors from forming o Histone modification Histones play an important role in coiling DNA (like a spool) that organizes DNA thread in order to help compact the DNA in the nucleus of the cell Can be acetylated or deacetylated which could result in alterations of gene expression Chromatin: DNA association with histones Plays a critical role in determining the development of cells, the cell lineage o So if there are mutations in the genes that encode histones, it ends up modifying proteins- associated with congenital heart disease o If there is a mutation in the part of the histone that coils the DNA, it can either up regulate or down regulate gene expression (TEXT) Chemical modifications of histones in regios of DNA can either up regulate or down regulate nearby gene expression by increasing or decreasing the tightness of the interaction between and histones, thus modulating the extent to which DNA is accessible to transcription factors (LECT)Downregulation- cells decrease the quantity of cellular components like RNA (LECT)Up regulation- Increase the quantity of cellular components- cells become more sensitive to molecules through exposure to toxins in hormones Can lead to increase or decrease of how tight the DNA is spooled around the histone and if we have greater exposure of DNA strand it can cause problems. o Changes in the RNA mechanism Non coding RNA play a role in RNA splicing and DNA replication- they also act like sponges and sop up complementary RNA, thus inhibiting their function MicroRNA (miRNAs) are designed to modulate the stability and translational efficiency of the existing messenger RNAs o Translation when RNA decodes DNA and starts protein synthesis Can be specific enough so they do not bind to all messenger RNA and general enough to regulate large number of RNA sequences Directly moderates the translation by impairing ribosomal function and they regulate diverse signaling pathways so activity- can result in oncogenes and tumor suppressor genes. Epigenetics and Human Development o Embryonic stem cells are totipotent- have the ability to develop into any body or somatic cell o all cells have the same genes, but certain genes are only expressed in certain tissue types, so with normal epigenetic modification it would allow for these various differentiations in somatic cells ex: factor VIII expression takes place in liver cells. It would be in other cells but it is only functional in the liver ex 2: dopamine receptors present in all of our genes only expressed in neurons o all cells contain almost the same info and it it’s the EGM that enables cells to achieve all of those different functions o we have housekeeping genes remain active in almost all cells- they escape epigenetic silencing small percentage of genes need to have this ability in order to maintain function of all of the cells- need to be able to and are responsible for encoding of histones, DNA and RNA polymerases and ribosomal and RNA genes can be called on to restart or differentiate its cells when needed o Genomic Imprinting Imprinting of epigenetic regulation depends on whether the gene is inherited from mom or dad. Baby inherits 2 copies of each chromosome. One will remain active and one will be silenced. The one that is genetically silenced is imprinted Biallelic expression Both parents contribute to the phenotype Monoalleic Either maternal copy or paternal copy are selected for inactivation in some cells and the maternal copy is selected for in other cells Imprinted Copy inherited through sperm or egg is inactivated and remains inactive for life Genetic conflict hypothesis If we have genes that are imprinted maternally inherited genes tends to reduce offspring size Imprinting of paternally inherited genes tends to increase offspring size Prader-Willi and Angelman syndromes DNA looks identical but the manifestations of the phenotype is significantly differet Cause: Deletion of 4 million base pairs of long arm of chromosome 15 o If the gene is inherted from the father it is PW syndrome- phenotype is short stature, low muscle tone, small hands and feet, obese (due t lack of a feedback mechanism when it comes to feeling full, and mentally challenged. o If the gene deletion is inherited by the mother then we have a severely mentally chanllenged child, seizures, ant ataxic gait (fall a lot). Beckwith-Weidemann syndrome Manifestation would be identifiable at birth because the baby is larger than gestational age, hypoglycemic, have a large tongue, creases in earlobes, incomplete closure in the abdomialcavity risk for kidney tumor 20-30% cause by inheritance b 2 copies from the father and none from the mother called over expression of active insulin-like growth factor 2 (IGF-2) Russell-Silver syndrome 1/3 caused by imprinting abnormality of chromosome 11p15.5 Manifestation involve growth retardation, leg length discrepancies, and a small triangular face 10% of individuals with this disorder receive 2 copies of IGF2 and downregulation of active IGF2 causes diminished growth Epigenetics and Nutrition o Can be related to nutritional deprivation in one or more generations In utero exposure to chemicals may lead to similar epigenetic modifications Nutritional deprivation while in utero can result in obesity later in life and may be smaller as well Epigenetics and Maternal Care o Parenting style can affect epigenetic states o Alteration to methylation states could help explain why exposure to stress early in life can modulate behavior in adulthood Epigenetics and Ethanol Exposure During Gestation o Fetal alcohol syndrome Alcohol exposure during fetal development can lead to DNA methylation states and this can impair fetal expression of DNA methyltransferase- greater DNA methylation Treatment with ethanol impairs cultured stem cells’ ability to differentiate to functional neurons Ethanol exposure in utero may repress fetal expression of the DNA methyltransferases Epigenetic Disease in Context of Genetic Abnormalities o Result from gain or loss if EGM Fragile X syndrome Arises through a gain of abnormal methylation o Sections in the gene that repeat CG sequencing more than it should (FMRI promoter) Disease can be present in males with the large repeat and absent in others with similar large repeats Acquisition of methylation-based silencing at FMRI is stochastic Fascioscapulohumeral muscular dystrophy (FSHMD) Normal lifespan but at that age they become wheelchair dependent later in life Arises through loss of normal methylation (less dense methylization) Deletion of a nucleotide repeat in the DUX4 gene Twin studies o Helpful because when we are thinking of identical twins, it is easier to spot EGM The way they look can change over time. Exposure to environmental chemicals and stressors Molecular Approaches to understanding Epigenetic disease o Epigenetic information is encoded by chemical modifications to these molecules- it can be quantified Bisulfate conversion can help us tally how much methylated and unmethylated cysteines there are We can also tell how much of the histones have been modified by examining the antibodies that are specific to the histones Epigenetics and Cancer o DNA methylation Hypomethylation in a normal individual Tumor cells have a lack of methylation, so tumor suppression gees have dense DNA methylation, when that level is lower this is what gives rise to cancer RB1 gene hyper methylated there is a lesser chance of getting BRCA1 comes from hypomethylated genes and gives rise to inherited breast cancers Colon cancers comes from Methylates MCH1 tumor suppresser o Micro RNA thought to play a role in the development of cancer Encodes small RNA molecules that bind to the ends of mRNA so if they are degraded this prevents translation of the proteins. When microRNA genes are methylated, their mRNA targets are overexpressed Associated with metastasis o Strategies for treatment of epigenetic disease Some chemical therapeutics might reverse changes associated with disease phenotype DNA demethylating agents o 5- way to address DNA methylation (leukemia and pancreatic cancer) cytosine is easily methylated in the 5 position of the ring, so this chemical adds a nitrogen in this spot so it can’t be methylated Histone deacetylase inhibitors o Reduces transcription activity- results in the inactivation of tumor suppressing genes HDI combats this miRNA coding o Targeting microRNAs and it is underway o Epigenetic screening for cancer Shows promise as a tool for early cancer diagnosis CHAPTER 4 Altered Cellular and Tissue Biology Cellular Adaptation and Injury Cellular adaptation o Physiological or pathogenic responses to stressors Physiological responses are adaptive vs. as a result of injury or stress our cells don’t respond in an adaptive way and lead to disease or injury 5 types of responses Atrophy o Decrease in cellular size due to a decrease in workload, pressure, use, blood supply, nutrition, hormonal stimulation, and nervous system stimulation Ex: cytoplasmic membrane has shrunk. They receive stimulation (either neuronal or hormonal, by O g2ucose levels, amino acids and other substances) and if they receive less stimulation they will atrophy Basically a response to chronic lack of resources number of cells remains the same! o Reversible adaptation Example: muscle cells- immobilization leads to muscle cell atrophy (thin legs of those wheel chair ridden) Hypertrophy o Increase in cellular size in post mitotic cells (past point where they can differentiate) if there is an increase demand the cells will hypertrophy The cells of the heart and kidney are particularly prone to enlargement Example: in heart failure the muscles hypertrophy, when you work out a lot your muscles get bigger o reversible Hyperplasia o Increase in number of cells due to increased rate of cellular division o Caused by increased stimulation over a period of time o Can be normal or pathological Normal: wearing shoes they don’t fit correctly and you develop a corn/callus forms (increase in cells to form more tissue to make your shoes fit better Menstrual cycle- normal buildup of uterine lining Pathological- benign prostatic hyperplasia- prostate begins to grow more cells and it takes up a lot of space. Can have overgrowth of endometrium and results in abnormal menstrual bleeding Dysplasia o Deranged cellular growth (not good) o Cell shape can change due to the body’s response to chronic irritation (frequent infection so the cells adapt by varying size and shape, can lead to the development of cancer) Classified as mild, moderate or high, and also low grade or high grade dysplasia Metaplasia o Replacement of one type of cell with another o One cell type is replaced by another in order to better withstand the injury- chronic irritation, infection, or injury The original cells die, the progenitor cells in the tissue select ones that are better able to withstand the injury type Example- normal ciliated bronchial columnar epithelial cells when subjected to chronic cigarette smoke are replaced by (non ciliated) stratified squamous epithelial cells. o Can be reversible if the irritation ceases. If the person stopped smoking, eventually their normal ciliated bronchial epithelial cells would return o If the irritation continues the cells might be replaced with malignant cells Cellular injury o Reversible and irreversible If reversible the cells can recover and continue to function Reversible injuries are in response to mild and temporary injuries in whicht e cell has time to recover If irreversible, the cells die If the injury is bad enough, or continues for long enough, the cells will die and the damage will not be reversible o 4 types of injury Toxic (chemical) Caused by xenobiotics (things that don’t belong in our body) o Carbon tetrachloride (use to be in detergents) o Lead no safe level! Use to be in gas and paint Really affects children because they put things in their mouth and if their toy has lead paint, the lead is going straight into their systems, more exposure. Children have ales developed blood brain barrier, and infants have a greater ability to absorb lead into their body and incorporate it in their bones o Carbon monoxide odorless, tasteless, o Ethanol o Mercury Source of heavy medal poisoning, so pregnant women should be careful on their mercury consumption o Social or street drugs Also caused by OTC drugs, prescribed medications, o can lead to accidental child poisoning, can disrupt critical ular structures, chemo therapeutic drugs target the cancer cells while inadvertently killing other cells that rapidly divide, o Hypersensitive reactions from mild skin reactions to immune-mediated organ failure Physical Unintentional/accidental Intentional trauma o Can be directly damaged or tissue can respond to damage by its neighboring cells o Blunt force that can result in tearing, shearing, or crushing of tissues Ex: MVA and falls Can also result in contusions (bruised), lacerations (cuts), and fractures (bone breakage) o Sharp force injuries Stabs, incised wound, puncture wood, chopping wound, gunshot wound (GSW) o Asphyxia injuries Body has been depried of oxygen as a whole Suffocation Choking, mothering Strangulation Hanging, ligature, and manual strangulation Chemical asphyxiates (take them and suddenly they can’t incorporate oxygen into the body) Cyanide and hydrogen sulfide Drowning Infectious/inflammation Pathogenicity of a microorganism Disease-producing potential o Invasion and destruction o Toxin production o Production of hypersensitivity reactions calls are injured by direct contact with cellular or chemical components, or by a neighbor that is undergoing this response o Immune response: lymphocytes, macrophages, histamines, antibodies, lymphokines, complement and protease Complement has its own cascade associated with the inflammatory process o Consequences Rapid leakage of K from the cells and an influx of water Antibodies can disrupt cell membrane function by binding at receptor cites where something else was supposed to bind can hinder cell communication in this way as well Deficits (water, oxygen, nutrients) Hypoxic injury is the most common cause of cellular injury ad result from a reduced amount of oxygen, Loss of hemoglobin (loss of blood leads to a loss of vehicles to carry the O 2 or decreased efficacy of hemoglobin (if the vehicle for carrying oxygen is ineffective, there will be no oxygen being transported), Decreased production of red blood cells (less vehicles to carry the O2), Diseases of the respiratory and cardiovascular systems, Poisoning of the oxidative enzymes (cytochromes) within the cells Hypoxic injury o Injuries that occur when there isn’t sufficient oxygen Reduced amount of oxygen, loss of hemoglobin, decreased efficiency, decreased production (anemic), respiratory or cardiovascular disease, poisoning by oxidative enzymes o Most common cellular injury o Production of ATP is reduced because you need O2 to make a lot of ATP. This leads to a failed Na/K pump that keeps the balance and Na will try to enter the cell, and water enters which is called vacuolation. K will rush out--> causes an acidic environment due to the ion balance differences between inside and outside the cell. Calcium that enters the cell will activate enzymes that damage cell membranes. Also can denature proteins Mitochondria and organelles swell and burst Entire cell may rupture o Ischemia Most common cause of hypoxia Ischemic injuries can happen when there is a thrombus (blocks coronary artery an those cells are not getting enough oxygen) Pt will be put on clot buster andwill get a stent, there is additional injury done when blood and o return Oxidative stress cause by free radicals (reactive O species) electrically uncharged molecule atom or group of atoms with unpaired electro the electron is the problem bc it really wants to bond and can form harmful bonds with proteins (bonds selectively) and disrupts normal cells function o Can bond with cell membrane, DNA and RNS which can result in harmful alterations to all Lipid peroxidation- destruction of lipids and cell membrane damage, and increased permeability o Can activate intracellular signaling pathways in an inappropriate manner Can increase intracellular Ca (doesn’t belong in the intracellular environment) Can cause inflammation Manifestation of cellular injury o One of the main manifestations are cellular accumulations or infiltrations Infiltrations can stem from normal cells that have inefficient functioning or damaged cells Accumulations of normal cellular substances and sometimes cellular swelling is reversible Early manifestations can demonstrate cellular injury Water entering the cell as a result of injury is not good and it is in response to the ion pump not working Fatty infiltrates (fatty or alcoholic liver syndrome) excessive fat storage, not good for the body CNS if there is too much fat in the CNS cells it can lead to neurological dysfunction and intellectual disability Glycogen storage (abnormal metabolism in glucose there to much glycogen store in the liver and subsequent use of that glycogen is inappropriate o Diabetes mellitus Type II) Inappropriate accumulations of protein in the cell when they are in the intracellular environment they can push organelles aside and disrupt cellular function o Renal tubules accumulate protein we can have too much accumulation in the B lymphocytes (Russell bodies) Scientists are now seeing connections between Russel bodies and multiple myeloma Pigments in the cells are often normal but there can be abnormal manifestations Endogenous (normal) pigments include melanin, hemoproteins, and bilirubin o Hemoproteins- bruising Blood vessels are damages and RBC leak near the break (extravasated), then they are phagocytized by macrophages, hemoglobin from the phagocytosis of RBC is converted to hemosiderin and iron pigments Exogenous (not normal) could include coal dust or carbon o Have to do with industrial exposures Calcium may be a manifestation in dead and dying tissues, called dystrophic calcification o Metastatic- mineral deposits associated with hypercalcemia (associated with addison’s disease, toxic levels of vitamin D, and hyperthyroidism o Ca is generally in the mitochondria and ER and pumped out of the cells when it is bound to calcium binding proteins. When there is damage there is free calcium floating around, and it can have 4 outcomes: activates protein kinases which can end up with phosphorylation of protein and chromatin fragments. activate phospholipases with phospholipid degradation and loss which leads to cell membrane damage protease activation with cell swelling and results in cytoskeletal disassembly. And activation of endonuclease which results in nucleus chromatin damage Urate- accumulations of uric acid and can be stores in the joints called gout o Lysosomes do not degrade the uric acid and it persists in the cells. Some medications help convert it and reduce it Systemic manifestations o How we know there are cell injury o Fever associated with infectious injury o Increased HR o Increased leukocytes Their job is to fight against infectious invaders o Pain o Presence of enzymes When we do blood tests in the acute care system, they look for these enzymes because it is a sign that cell injury has taken place Creatinine kinase check if there has been injury to cardiac cells, can also be a sign of injury elsewhere, but mostly in the cardiac cells
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